Store-Operated Calcium Channels

<jats:p>In electrically nonexcitable cells, Ca<jats:sup>2+</jats:sup>influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca<jats:sup>2+</jats:sup>entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca<jats:sup>2+</jats:sup>stores activates Ca<jats:sup>2+</jats:sup>influx (store-operated Ca<jats:sup>2+</jats:sup>entry, or capacitative Ca<jats:sup>2+</jats:sup>entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca<jats:sup>2+</jats:sup>release-activated Ca<jats:sup>2+</jats:sup>current, I<jats:sub>CRAC</jats:sub>. Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I<jats:sub>CRAC</jats:sub>-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca<jats:sup>2+</jats:sup>content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca<jats:sup>2+</jats:sup>sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca<jats:sup>2+</jats:sup>entry. Recent work has revealed a central role for mitochondria in the regulation of I<jats:sub>CRAC</jats:sub>, and this is particularly prominent under physiological conditions. I<jats:sub>CRAC</jats:sub>therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I<jats:sub>CRAC</jats:sub>and other store-operated Ca<jats:sup>2+</jats:sup>currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca<jats:sup>2+</jats:sup>entry pathway.</jats:p>